Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide; also referred to as 4-HPR), which has CAS registry number 65646-68-6, is a synthetic retinoid. Fenretinide was initially developed as a less toxic and better tolerated derivative of retinoic acid and has been extensively studied because of its chemo-protective and anti-tumor activities described when used on a variety of malignant cells, including non-small cell lung cancer, neuroblastoma, Kaposi's sarcoma, breast cancer and glioma (Charles, et al. (2001) Cancer Chemother. Pharmacol. 47:444-450; Garaventa, et al. (2003) Clin. Cancer Res. 9:2032-2039; Lippman, et al. (2001) J. Natl. Cancer Inst. 93:605-618; Ponthan, et al. (2003) Oncol. Rep. 10:1587-1592; Puduvalli, et al. (1999) Clin. Cancer Res. 5:2230-2235; Rao, et al. (1998) Breast Cancer Res. Treat. 48:265-271), and has been approved for clinical trials of cancer patients. However, despite its promising anticancer activity in preclinical studies, its limited oral bioavailability, notably due to its poor water solubility, represents a significant challenge for its clinical assessment.
Fenretinide has been formulated in corn oil-containing soft-gelatin capsules, but such formulations have been shown to result in variable and low systemic exposures (i.e. poor bioavailability). Also, because of their size, patient compliance has been shown to be a concern with these corn oil-containing capsules, especially in pediatric subjects. Fenretinide has also been formulated in a lipid matrix, Lym-X-Sorb (LXS), (Maurer B J, Clin Cancer Res 13: 3079-3086, 2007), administrated as an oral powder delivered in non-milk fat-containing foods, and especially as a slurry in non-milk fat-containing, or soy-based nutritional supplements. However, this formulation has been shown to be associated with significant gastrointestinal (GI) side-effects, especially at higher doses (Kummar et al. (2011) Anticancer Research 31(3):961-966), as well as to significant patient withdrawal due to the taste and texture of the medication.
There is thus a need for new pharmaceutical compositions of fenretinide, especially for oral administration, capable to overcome the poor oral bioavailability of corn-oil based formulation, while allowing for more compliant pharmaceutical dosage forms such as hard gelatine capsules, tablets, strips, caplets, suspensions, or powders for suspensions.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.